The long-term goal of this research program is to develop sensitive and specific high-resolution in-vivo magnetic resonance (MR) metabolic imaging techniques to study small animal models of ischemic attack, and to integrate in-vivo metabolic imaging with ex-vivo molecular imaging. The specific goals of this proposal are: 1) to develop a high-resolution MR imaging sequence sensitive to changes in susceptibility following ischemia; 2) to develop a high-resolution metabolic imaging sequence to produce quantitative maps of lactate (a byproduct of anaerobic glycolysis) and N-acetylaspartate (a putative marker of neuronal viability); and 3) to integrate these in-vivo imaging techniques with ex-vivo molecular images of cleaved-caspase-3 (a marker of apoptosis) and heat-shock-protein-70 (HSP70, a marker of cell stress). High-resolution diffusion/susceptibility imaging will be developed based on the LASER pulse sequence and the contrast directly compared to conventional diffusion imaging. Contrast sensitivity to microscopic susceptibility in the LASER sequence will be tested in a small animal model with the infusion of an iron oxide based contrast agent (MION) and enhanced by adding conventional diffusion weighting gradients. High-resolution quantitative metabolic images will be based on the LASER sequence, incorporating frequency selective excitation, outer volume suppression, and macromolecule nulling. In-vivo imaging techniques will be integrated with molecular imaging using advanced non-linear image warping and registration. A paradigm will be developed to monitor the in-vivo evolution of metabolic, susceptibility, and ionic (sodium) markers from distinct molecular regions undergoing pathological processes including apoptosis, necrosis, and activation of immediate early genes (HSP70). These novel techniques will form the basis for biologists and pharmaceutical scientists to develop and rapidly test the efficacy of novel therapeutic neuroprotective agents to preserve brain tissue viability following an ischemic attack.